Nitric oxide is an important inter- and intracellular messenger implicated in the pathogenesis of septic shock. Inhibition of nitric oxide synthase is under investigation as a treatment for hypotension in septic shock. In addition to the vasodilating effect of nitric oxide, this messenger also has effects on platelets and immune cells. In this investigation, we are examining the role of the nitric oxide pathway as a modulator of immune cell function. We have been unable to create conditions under which human phagocytes, in particular neutrophils, endogenously produce nitric oxide (J Immunol: 1825, 1994). Therefore, the ability of nitric oxide produced by other cells, such as endothelium and epithelium, to alter the function of human phagocytes is being explored.We have confirmed that nitric oxide regulates cytokine production using a U937 monocytic cell line transfected to express murine-inducible nitric oxide synthase (Blood: 1160, 1997). Further investigation of this effect has resulted in the description of a cGMP-independent signaling pathway for nitric oxide (J Biol Chem: 5959, 1997). We have found that in addition to upregulating TNFa production (J Immunol: 4102, 1994), nitric oxide modulates IL-8 message transcription and release in human neutrophil preparations. However, contrary to other reports, we have found that nitric oxide does not directly alter neutrophil chemotaxis (J Infect Dis: 116, 1998). Recent work has identified a no-response element in the TNFa promoter (manuscript in preparation). Future experiments are planned to better characterize this signal transduction pathway, in both U937 cells and freshly isolated human phagocytes, and to document its effect on cell function and differentiation.